The autoimmune thyroid diseases (AITD) are very common with a prevalence of - 5 percent. They include Hashimoto's thyroiditis (HT), which manifests by hypothyroidism, and Graves disease (GD), which causes hyperthyroidism. The mechanisms initiating the AITD are not completely understood. Abundant data point to a genetic susceptibility to AITD, and the applicant, has identified linkages for several AITD susceptibility loci. In the past four years we have performed genome scans on two data sets of multiplex families (102 families, 540 individuals), and mapped 8 loci showing evidence for linkage with AITD. In two of the loci we identified and investigated putative AITD susceptibility genes (CTLA-4 and CD4O}. The focus of the current proposal is four of the eight loci which showed the strongest evidence for linkage with AITD. The goals of our study are to identify and characterize the AITD susceptibility genes in these four loci. The specific aims of the proposed study are: 1) To resolve the genetic heterogeneity in our families at the 4 linked loci which are the focus of our studies. At all 4 loci the linkage analysis showed evidence of heterogeneity and resolving it will facilitate identification of the AITD susceptibility genes. We will subdivide the families according to various parameters (e.g. age of onset of disease), analyze these subsets separately for linkage with the four loci, and apply the Predivided-Sample Test. Resolving heterogeneity and identifying subsets of families that are uniformly linked with these loci will amplify the power of the subsequent single nucleotide polymorphism (SNP) and fine mapping analyses (Specific Aims 2 & 3); 2) To analyze two important genes (thyroglobulin and TGFBeta3 which are located at 2 of the linked loci, and are themselves linked and associated with AITD. We will analyze the sequences of the thyroglobulin and TGF-Beta3 genes in order to identify disease-specific SNP's; 3) To fine map two additional linked loci and narrow the linked regions in order to determine appropriate candidate genes for future analyses. We have the capacity and experience to perform these studies. Our flexible relational database (lngresTM) facilitates complex linkage and association analyses. We use two ABI-310 sequencers for genotyping and sequencing, and we have experience at SNPing genes and fine mapping linked regions. We expect that these studies will lead to the identification of gene sequence variations contributing to the expression of AITD. This will allow us to understand the mechanisms initiating these diseases, and hopefully will lead to the development of new therapies targeted at the mechanisms initiating AITD.